Process for the preparation of compounds derived from 4-(3-ethoxy-4-hydroxyphenyl) but-2-one

Abstract

The present invention relates to a process for the preparation of one or more compounds derived from 4-(3-ethoxy-4-hydroxyphenyl) but-2-one corresponding to the following formula (I), as well as the optical isomers or geometric isomers thereof, and also the salts thereof with alkaline agents, and / or the solvates thereof, such as hydrates thereof. The invention also relates to one or more specific compounds derived from 4-(3-ethoxy-4-hydroxyphenyl) but-2-one corresponding to the formula (I ') as defined below.

Description

[0001] The present invention relates to a method for preparing one or more compounds derived from 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one corresponding to formula (I) as described below, as well as their optical or geometric isomers, and also their salts with organic or inorganic acids or bases, and / or their solvates such as hydrates.

[0002] The present invention also relates to one or more specific compounds derived from 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one corresponding to formula (I') as defined below.

[0003] Microorganisms can relatively easily survive and spread in cosmetic, dermatological, pharmaceutical and food products that do not contain preservatives.

[0004] Therefore, preservatives are regularly added to most industrial formulations intended for storage or preservation in order to prevent microbial growth over time. Microbial contamination is also common during the production of industrial products, even when the starting ingredients of the product are "clean", i.e., free of contaminating microorganisms.

[0005] For example, water, which is ubiquitous in most cosmetic, pharmaceutical, dermatological or even nutritional preparation products, must be free of contaminating microorganisms. Similarly, other ingredients must also be screened for the presence of contaminating microorganisms. The cleanliness must be strictly monitored during the production of these industrial products, the handling of the contents and the filling of the containers in order to minimize or even eliminate the presence of contaminating microorganisms.

[0006] Despite these precautions, the microbial integrity of this type of product may require the presence of one or more preservatives (preserving agent or preservative) compatible with the product and the stability of the composition. The product must not allow the growth or viability of contaminating microorganisms.

[0007] Furthermore, since fingers, applicators (such as cosmetic applicators) and even the ambient air are not sterile, maintaining cleanliness during the use of such products remains problematic, especially when they are being grasped. Therefore, preservatives are proven to be necessary in order to reduce microbial contamination by consumers during normal use.

[0008] Generally speaking, all products sold (especially cosmetic products) must be free of pathogenic microorganisms (Kirk Othmer Encyclopedia, Cosmetics, Martin M. Rieger, 04 / 12 / 2000). In recent years, the preservation problem has also led to the introduction of preservatives with different spectra of action in order to combat resistant contaminating microorganisms.

[0009] The compound 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one (also known as ethyl gingerone (EZ)) is a preservative commonly used in compositions, especially cosmetic compositions, due to its favorable properties against various bacterial strains (both Gram-positive and Gram-negative) on fungi and yeasts. This compound also exhibits high activity against bacteria of the Burkholderia cepacia complex.

[0010] The compound 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one is usually used alone or as a mixture with other preservative or non-preservative compounds to effectively protect various compositions, especially cosmetic compositions, from microbial contamination during their preparation and during use in daily life.

[0011] The compound 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one can be prepared from ethyl vanillin especially through the following synthetic route ( A ):

[0012]

[0013] In the synthetic route ( A ):

[0014] - R2 represents a hydrogen atom and R3 represents a straight-chain (saturated) C1-C6 alkyl group optionally substituted by a hydroxyl group; or a straight-chain C2-C6 alkenyl group (C=C unsaturated), or alternatively a straight-chain C2-C12 alkenyl group substituted by a hydroxyl group;

[0015] - Or R2 represents a methyl or ethyl group, and R3 represents a straight-chain (saturated) C1-C6 alkyl group optionally substituted by a hydroxyl group; or a straight-chain C2-C6 alkenyl group (C=C unsaturated), or alternatively a straight-chain C2-C12 alkenyl group substituted by a hydroxyl group.

[0016] According to this reaction scheme, the method for preparing the compound 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one includes at least the following consecutive steps: a) at least one step of reacting ethyl vanillin with at least one carbonyl compound in the presence of sodium hydroxide and water to produce a compound of the following formula (W):

[0017]

[0018] b) at least one step (b) of hydrogenating the compound of formula (W) in the presence of at least one palladium (Pd) carbon catalyst under a pressure of about 10 bar to produce ethyl gingerone.

[0019] Process (A) for the preparation of a compound of formula (I), in particular a compound of formula (I”) 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one, does not give a fully satisfactory yield by conventional preparation methods (see, for example, WO 2011 / 039445; J. Asian Natural Products Research, 8(8), 683-688 (2006); Helv. Chimica Acta, 89(3), 483-495 (2006); Chem. Pharm. Bull., 54(3), 377-379 (2006); and Bioorg. Med. Chem. Lett., 14(5), 1287-1289 (2004)), and its implementation requires further optimization, particularly in terms of the number of steps and / or product quality on an industrial scale. In addition, the compound of formula (I) and in particular the compound of formula (I”) has its characteristic eugenol (especially clove) spicy-round vanilla type of odor. However, this preparation method (A) has the disadvantage of generating impurities, some of which have a distinct odor, especially a strong metallic and fused character, which is very unpleasant and proves to be particularly difficult to eliminate. This unpleasant odor is especially due to the presence of 2-ethoxy-4-n-butylphenol, whose odor has these unwanted strong metallic fused odors. In most cases, this unpleasant and persistent odor dominates the overall round vanilla odor of 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one, which is incompatible with the industrial scale development of applications, especially cosmetic applications. This also applies to other less odorous impurities, such as 2-ethoxy-4-(3-hydroxybutyl)phenol, the amount of which is desired to be minimized or even eliminated at the end of the preparation method.

[0020] In particular, reaction step (a) gives rise to a certain number of impurities, especially dimers, in particular dimers of the compound of formula (W), dimers of carbonyl compounds and mixed dimers resulting from the reaction between the compound of formula (W) and carbonyl compounds. In addition, once reaction step (i) is completed, the reaction medium may still contain residual ethyl vanillin that has not reacted with the carbonyl compound.

[0021] Such impurities, dimers or other impurities may also cause other impurities that are liable to have a distinct and unpleasant odor during reaction step (b) (hydrogenation step).

[0022] Therefore, different purification operations are used, such as by washing, recrystallization, and / or repulping (either once or even several times in succession), so as to reduce or even eliminate, once the reaction step (a) is completed, the dimer impurities and other impurities from the reaction medium, as well as the remaining ethyl vanillin.

[0023] However, such purification operations (including those carried out several times in succession) do not significantly improve the purity obtained at the end of reaction step (a).

[0024] More generally, such purification operations carried out at the end of reaction step (a) and reaction step (b) cannot reduce or even eliminate the impurities generated during the preparation of ethyl levulinate and / or its derivatives (including the impurities that produce unpleasant and displeasing fusion and metal eugenol odors), and have the drawback of reducing the yield.

[0025] Therefore, the methods conventionally used in the prior art for preparing 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one and / or its derivatives do not produce a sufficiently satisfactory purity and yield for reproducible and robust industrial-scale production, particularly in the cosmetic field.

[0026] In view of the above, therefore, there is indeed a need to implement a novel method for preparing 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one and / or a compound derived from 4-(3-ethoxy-4-hydroxyphenyl)butan-2-one corresponding to formula (I) as described below, which method does not have the above-mentioned drawbacks and, in particular, produces increased purity, higher yield and is further optimized in its implementation, particularly at the industrial level (in terms of the number of steps and / or the quality of the product at the industrial scale), without causing the release of unpleasant and unacceptable odors.

[0027] In particular, one of the objects of the present invention is to provide a method for preparing a compound of formula (I) as described below, during which impurities (including those having a distinct and unpleasant odor) can be minimized or even eliminated, so as to be effectively implemented on an industrial scale, particularly for cosmetic applications.

[0028] In other words, one of the objects of the present invention is to provide a method for preparing a compound of formula (I), the use of which does not result in the release of unpleasant odors, thus making it suitable for industrial applications, particularly cosmetic applications.

[0029] Therefore, the present invention particularly relates to a method for preparing at least one compound of the following formula (I):

[0030]

[0031] In formula (I):

[0032] -R 1 represents a straight-chain or branched-chain, saturated or unsaturated hydrocarbon group having 1 to 6 carbon atoms; preferably, R 1 represents a C1-C4 alkyl group, more preferably a C2-C4 alkyl group such as an ethyl group;

[0033] -R 2 represents a hydrogen atom or a C2-C4 alkyl group such as a methyl group or an ethyl group; preferably, R 2 represents a hydrogen atom;

[0034] -R 3 represents a straight-chain or branched-chain, saturated or unsaturated hydrocarbon group having 1 to 12 atoms optionally substituted by an aryl group; the aryl group is preferably a phenyl group optionally substituted by one or more groups selected from a hydroxyl group, a C1-C4 alkyl group, a C1-C4 alkoxy group, and combinations thereof; preferably, R 3 represents a C1-C6 alkyl group; preferably a C1-C4 alkyl group;

[0035] as well as one of its optical isomers or geometric isomers, and / or one of its salts with an organic or inorganic acid or base, and / or one of its solvates such as a hydrate;

[0036] The method is carried out according to the following synthesis scheme ( 1 ):

[0037]

[0038]

[0039] ■ In the synthesis pathway ( 1 ):

[0040] -X represents a heteroatom selected from oxygen and sulfur, preferably an oxygen atom,

[0041] -R 1 、R 2 and R 3 have the same meanings as in formula (I);

[0042] The method is characterized in that the method comprises:

[0043] - at least one step (i) of reacting a compound of formula (II) in the presence of the following:

[0044] ○ at least one compound of formula (III),

[0045] ○ at least one (non)polar (aprotic) solvent, and

[0046] ○ at least one basic agent in an amount in excess of the molar amount of the compound of formula (II),

[0047] so as to form at least one precipitate, the at least one precipitate comprising at least one compound of formula (IV), its geometric isomers and / or one of its salts with an organic or inorganic base; and

[0048] - at least one step (i1) of separating the precipitate from the reaction medium of step (i), and then

[0049] - at least one step (i2) of acidifying the precipitate with at least one inorganic or organic, preferably inorganic acidifying agent, followed by reaction step (ii).

[0050] In other words, once a precipitate (comprising at least the compound of formula (IV), its geometric isomers and / or one of its salts with an organic or inorganic, preferably inorganic base) is formed at the end of step (i), then the precipitate is separated from the reaction medium and then acidified with at least one inorganic or organic acidifying agent, followed by reaction step (ii).

[0051] After the separation step (i1) and the acidification step (i2), the compound of formula (IV) is used in the reduction step (ii) to produce the compound of formula (I).

[0052] Thus, the method according to the invention makes it possible to achieve the object described above, namely that it produces the compound of formula (I) with high purity in a satisfactory yield, while showing an optimized implementation at the industrial level, which is in particular robust and reproducible, especially with respect to the methods conventionally used in the prior art.

[0053] In particular, the method according to the invention has the advantage of minimizing or even eliminating impurities, including those that usually have a distinct and unpleasant odor, especially those that are particularly difficult to remove in the methods conventionally used in the prior art and that produce unpleasant odors with a metallic or smoky and woody odor.

[0054] Thus, the method according to the invention has the advantage of minimizing, or even eliminating, the unpleasant and disagreeable odors (especially those with a fused and metallic odor) that occur in the methods conventionally used in the prior art.

[0055] Thus, the method according to the invention makes it possible to produce a compound of formula (I) with high purity (greater than or equal to 95% as measured by HPLC).

[0056] Advantageously, separating the precipitate from the reaction medium at the end of step (i) makes it possible to envisage recycling a part of the excess base agent used in order to improve the performance of step (i).

[0057] The present invention also relates to a compound corresponding to the following formula (I'):

[0058]

[0059] In formula (I'):

[0060] -R 1 represents a straight-chain or branched, saturated or unsaturated hydrocarbon group containing 1 to 6 carbon atoms; preferably, R 1 represents a C1-C4 alkyl group, more preferably a C2-C4 alkyl group such as ethyl;

[0061] -R 2 represents a hydrogen atom or a C2-C4 alkyl group such as methyl or ethyl;

[0062] -R 3 represents a branched, saturated or unsaturated hydrocarbon group containing 1 to 12 carbon atoms, preferably R 3 represents a branched, saturated or unsaturated hydrocarbon group containing 3 to 12 carbon atoms; more preferably R 3 represents a branched C1-C6 alkyl group, more preferably R 3 represents a branched C3-C6 alkyl group; in particular, R 3 represents a branched C3-C4 alkyl group, especially a branched C4 alkyl group;

[0063] and also one of its optical isomers or geometric isomers, and / or one of its salts with an organic or inorganic acid or base, and / or one of its solvates such as a hydrate.

[0064] Furthermore, the present invention also relates to a composition which comprises, in a physiologically acceptable medium, at least one compound of formula (I') as described above, its salts and / or isomers and / or solvates.

[0065] Other subjects, features, aspects and advantages of the present invention will become even clearer and more apparent after reading the following description and examples.

[0066] In the following and unless otherwise indicated, the limits of the ranges of values are included within these ranges, especially in the expressions "between... and" and "ranging from... to...".

[0067] Furthermore, the expression "at least one / species" used in this specification is equivalent to the expression "one / species or more than one / species".

[0068] Furthermore, the expression "at least" used in this specification is equivalent to the expression "greater than or equal to". Finally, in a manner known per se, the term "C n " compound or group indicates a compound or group containing "n" carbon atoms in its chemical structure.

[0069] The HPLC purity corresponds to the relative purity expressed as a percentage of the area measured at the maximum absorption wavelength (λmax) of the product being analyzed.

[0070] Within the meaning of the present invention, the terms "basic agent" and "alkalinizing agent" are used interchangeably.

[0071] The alkalinizing agent can be an inorganic basic agent, preferably selected from the group consisting of: alkali metal hydroxides or alkaline earth metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, alkali metal carbonates (hydrogencarbonates) or alkaline earth metal carbonates (hydrogencarbonates), such as sodium carbonate (hydrogencarbonate) or potassium carbonate (hydrogencarbonate), and mixtures thereof. The alkalinizing agent can be an organic basic agent, preferably selected from the group consisting of: mono(C1-C6)(hydroxy)alkylamines, di(C1-C6)(hydroxy)alkylamines, tri(C1-C6)(hydroxy)alkylamines (preferably tri(C1-C6)(hydroxy)alkylamines), saturated or unsaturated cyclic amines, which are aromatic, such as pyridine, or optionally non-aromatic and optionally substituted by one or more (C1-C4)alkyl groups, such as tetrahydropyridine optionally substituted by one or more (C1-C4)alkyl groups, piperidine optionally substituted by one or more (C1-C4)alkyl groups, or piperazine optionally substituted by one or more (C1-C4)alkyl groups. Preferably, the basic agent of the present invention is a tertiary amine.

[0072] Preferably, the alkalinizing agent is selected from the group consisting of: alkali metal hydroxides or alkaline earth metal hydroxides, especially sodium hydroxide, alkali metal carbonates (hydrogencarbonates) or alkaline earth metal carbonates (hydrogencarbonates), especially sodium carbonate (hydrogencarbonate) or potassium carbonate (hydrogencarbonate), and tri(C1-C6)(hydroxy)alkylamines, especially tri(C1-C6)alkylamines, especially triethylamine.

[0073] More preferably, the alkalinizing agent is inorganic and selected from the group consisting of: alkali metal hydroxides or alkaline earth metal hydroxides, alkali metal carbonates (hydrogencarbonates) or alkaline earth metal carbonates (hydrogencarbonates), and mixtures thereof, especially alkali metal hydroxides or alkaline earth metal hydroxides, especially sodium hydroxide.

[0074] Preparation method

[0075] As indicated above, the process according to the present invention is carried out according to the reaction scheme as described above ( 1 ) and comprises:

[0076] -At least one step (i), which at least includes the reaction of at least one compound of formula (II) in the presence of at least one compound of formula (III), at least one (non)polar (non)protic solvent, and at least one base agent (present in an excess molar amount relative to the compound of formula (II)) such that a precipitate is formed, the precipitate comprising at least the compound of formula (IV), its geometric isomers, and / or one of its salts with an organic or inorganic base.

[0077] -At least one step (i1) of separating the precipitate from the reaction medium of step (i), and then

[0078] -At least one step (i2) of acidifying the precipitate using at least one inorganic or organic, preferably inorganic, acidifying agent, followed by reaction step (ii).

[0079] According to the invention, step (i) includes the reaction of the following:

[0080] -At least one compound of formula (II), wherein R 1 and X have the same meanings as those indicated above,

[0081] ○Preferably, in formula (II), X represents an oxygen atom,

[0082] In the presence of the following:

[0083] -At least one compound of formula (III), wherein R 2 and R 3 have the same meanings as those indicated above,

[0084] ○Preferably, in formula (III), R 2 represents a hydrogen atom and R 3 represents a C1-C6 alkyl group, preferably a C1-C4 alkyl group, preferably methyl or ethyl, especially methyl;

[0085] ○Advantageously, the compound of formula (III) is present in the reaction medium of step (i) in an amount less than or equal to 5 molar equivalents, more preferably in an amount ranging from 2 to 5 molar equivalents, still better in an amount ranging from 2.5 to 5 molar equivalents, especially in an amount of 4.5 molar equivalents, relative to the compound of formula (II) such that the kinetics of reaction step (i) can be improved;

[0086] -At least one (non)polar (non)protic solvent, preferably at least one polar protic solvent such as water,

[0087] ○ Preferably, as a mixture with the following: at least one (non)polar (non)protic organic solvent, preferably a (non)polar aprotic organic solvent such as a nonpolar aprotic organic solvent, which preferably has a low dielectric constant and dipole moment, preferably having a dielectric constant E in the range from 1 to 11 and a dipole moment μ in the range from 0 to 2, especially those selected from the group consisting of: n-hexane, cyclohexane, 1,4-dioxane, carbon tetrachloride (CCl4), benzene, tetrachloroethylene (Cl2C═Cl2C), toluene, carbon disulfide (CS2), trichloroethylene (Cl2C═CHCl), diethyl ether (Et2O), ethyl acetate (CH3C(O)OEt or AcOEt), dimethyl ether (DME), tetrahydrofuran (THF), methyltetrahydrofuran (2-MeTHF), dichloromethane (CH2Cl2), dichloroethane (ClCH2CH2Cl) and mixtures thereof;

[0088] - at least one organic or inorganic, preferably inorganic base agent,

[0089] ○ More preferably, the base agent is selected from the group consisting of: alkali metal hydroxides or alkaline earth metal hydroxides, alkali metal carbonates (hydrogencarbonates) or alkaline earth metal carbonates (hydrogencarbonates), and mixtures thereof, especially alkali metal hydroxides or alkaline earth metal hydroxides, especially sodium hydroxide;

[0090] - the base agent is in an excess molar amount relative to the compound of formula (II),

[0091] ○ Preferably, the amount of the base agent is greater than or equal to 2 molar equivalents, more preferably in the range from 2 to 5 molar equivalents, for example 4.5 molar equivalents, relative to the compound of formula (II);

[0092] so as to form at least one precipitate, which at least one precipitate comprises at least the compound of formula (IV), its geometric isomers and / or one of its salts with an organic or inorganic base.

[0093] Preferably, the base agent in step (i) is an inorganic base agent selected from the group consisting of: alkali metal hydroxides or alkaline earth metal hydroxides, alkali metal carbonates (hydrogencarbonates) or alkaline earth metal carbonates (hydrogencarbonates), and mixtures thereof, especially alkali metal hydroxides or alkaline earth metal hydroxides, especially sodium hydroxide.

[0094] Preferably, the base agent in step (i) is an inorganic base agent selected from the group consisting of alkali metal hydroxides or alkaline earth metal hydroxides, especially sodium hydroxide.

[0095] Preferably, the base agent in step (i) is an inorganic base agent selected from the group consisting of alkali metal hydroxides or alkaline earth metal hydroxides, especially sodium hydroxide, and is present in an amount of greater than or equal to 2 molar equivalents relative to the compound of formula (II), more preferably in an amount ranging from 2 to 5 molar equivalents.

[0096] Preferably, step (i) is carried out at a temperature of less than or equal to 40 °C, preferably at a temperature ranging from 20 °C to 35 °C, more preferably at a temperature ranging from 25 °C to 35 °C, especially at a temperature of 30 °C ± 1 °C, which enables improvement of the kinetics and quality of the reaction in step (i), especially the quality of the compound of formula (IV).

[0097] Advantageously, step (i) is carried out at a temperature of less than or equal to 40 °C, preferably at a temperature ranging from 20 °C to 35 °C, more preferably at a temperature ranging from 25 °C to 35 °C, especially at a temperature of 30 °C ± 1 °C, and the base agent is present in an amount ranging from 2 to 5 molar equivalents relative to the compound of formula (II), which also enables improvement of the kinetics and quality of the reaction in step (i).

[0098] Advantageously, step (i) is carried out at a temperature of less than or equal to 40 °C, preferably at a temperature ranging from 20 °C to 35 °C, more preferably at a temperature ranging from 25 °C to 35 °C, especially at a temperature of 30 °C ± 1 °C for a period ranging from 30 minutes to 24 hours, preferably ranging from 6 hours to 18 hours, more preferably ranging from 10 hours to 15 hours, and especially 12 hours.

[0099] Advantageously, step (i) is carried out by:

[0100] - at least one base agent as defined above, in an amount ranging from 2 to 5 molar equivalents relative to the compound of formula (II),

[0101] - at a reaction temperature of less than or equal to 40 °C, preferably at a temperature ranging from 20 °C to 35 °C, more preferably at a temperature ranging from 25 °C to 35 °C, especially at a temperature of 30 °C ± 1 °C,

[0102] - for a period ranging from 30 minutes to 24 hours, preferably ranging from 6 hours to 18 hours, more preferably ranging from 10 hours to 15 hours, especially 12 hours.

[0103] Preferably, step (i) is carried out in the presence of at least one compound of formula (II) and:

[0104] - at least one compound of formula (III), present in an amount ranging from 2 to 5 molar equivalents,

[0105] ○ More preferably, the amount ranges from 2.5 to 5 molar equivalents, especially 4.5 molar equivalents, relative to the compound of formula (II);

[0106] - At least one (non)polar (aprotic) solvent, preferably at least one polar protic solvent such as water,

[0107] ○ Optionally as a mixture with at least one nonpolar aprotic organic solvent,

[0108] - At least one inorganic base agent, which is preferably selected from the group consisting of alkali metal hydroxides or alkaline earth metal hydroxides, alkali metal carbonates (hydrogencarbonates) or alkaline earth metal carbonates (hydrogencarbonates), and mixtures thereof. The amount ranges from 2 to 5 molar equivalents, especially 4.5 molar equivalents, relative to the compound of formula (II);

[0109] - At a temperature of less than or equal to 40 °C, preferably in the range from 20 °C to 35 °C, more preferably in the range from 25 °C to 35 °C, especially at a temperature of 30 °C ± 1 °C.

[0110] Advantageously, step (i) is carried out in the presence of at least one compound of formula (II) in the following:

[0111] - At least one compound of formula (III), which is present in an amount of 4.5 molar equivalents relative to the compound of formula (II),

[0112] - At least one polar protic solvent such as water, optionally as a mixture with at least one nonpolar aprotic organic solvent,

[0113] - At least one inorganic base agent, which is selected from the group consisting of alkali metal hydroxides or alkaline earth metal hydroxides. The amount ranges from 2 to 5 molar equivalents relative to the compound of formula (II);

[0114] - At a reaction temperature in the range from 20 °C to 35 °C, more preferably in the range from 25 °C to 35 °C, especially at a temperature of 30 °C ± 1 °C,

[0115] - The reaction time varies from 6 hours to 18 hours, preferably from 10 hours to 15 hours, and especially 12 hours.

[0116] In particular, the reaction step (i) of the process according to the invention is carried out at atmospheric pressure (1.013×10 5 Pa).

[0117] Preferably, the reaction step (i) of the process according to the invention is carried out under mechanical stirring.

[0118] Preferably, reaction step (i) of the process according to the invention is carried out in an industrial reactor, in particular a metal reactor.

[0119] Preferably, reaction step (i) of the process according to the invention is carried out by:

[0120] - adding the base agent as defined above, preferably an aqueous solution comprising at least the base agent, to a reaction medium comprising at least one compound of formula (II), at least one compound of formula (III) and at least one (non)-polar (non)-protic solvent, preferably a polar protic solvent such as water, preferably to an aqueous solution comprising at least one compound of formula (II) and at least one compound of formula (III),

[0121] - or adding at least one compound of formula (II), at least one compound of formula (III) and at least one (non)-polar (non)-protic solvent, preferably at least one polar protic solvent such as water, to a reaction medium comprising at least the base agent and at least one polar protic solvent such as water,

[0122] - or adding at least one compound of formula (II) and a solution comprising at least one polar protic solvent such as water and at least the base agent simultaneously to a reaction medium comprising at least one compound of formula (III), at least one polar protic solvent such as water and at least the base agent; preferably, the base agents are the same.

[0123] Advantageously, reaction step (i) of the process according to the invention is carried out by: adding the base agent as defined above, preferably an aqueous solution comprising at least the base agent, to a reaction medium comprising at least one compound of formula (II), at least one compound of formula (III) and at least one (non)-polar (non)-protic solvent, preferably a polar protic solvent such as water, preferably to an aqueous solution comprising at least one compound of formula (II) and at least one compound of formula (III).

[0124] According to this advantageous embodiment, the chemical degradation of the base agent with respect to the compound of formula (II) and / or the compound of formula (III) is thus minimized over time.

[0125] In particular, this chemical degradation of the base agent with respect to the compound of formula (II) and / or the compound of formula (III) can be observed due to the appearance of a brown color over time, which can be monitored by chromatography, preferably by HPLC chromatography, in particular with a UV detector.

[0126] As a variant, reaction step (i) of the process according to the invention can be carried out by simultaneously adding at least one compound of formula (II) and a solution comprising at least one polar protic solvent such as water and at least one base agent to a reaction medium comprising at least one compound of formula (III), at least one polar protic solvent such as water and at least said base agent; preferably, the base agent is the same.

[0127] Preferably, during step (i), the addition of the base agent is carried out over a period ranging from 10 minutes to 3 hours, more particularly over a period ranging from 30 minutes to 1 hour 30 minutes, especially within one hour, preferably at a temperature below or equal to 40 °C, preferably at a temperature ranging from 25 °C to 32 °C, especially at a temperature of 25 °C.

[0128] In other words, preferably, the addition time of the base agent varies from 10 minutes to 3 hours, more particularly over a period ranging from 30 minutes to 1 hour 30 minutes, especially within one hour, preferably at an addition temperature below or equal to 40 °C, preferably at an addition temperature ranging from 25 °C to 32 °C, especially at an addition temperature of 25 °C.

[0129] Preferably, once the base agent has been added to the reaction medium of step (i), the reaction medium is maintained at a temperature below or equal to 40 °C, preferably at a temperature ranging from 20 °C to 35 °C, more preferably at a temperature ranging from 25 °C to 35 °C, especially at a temperature of 30 °C.

[0130] Preferably, reaction (i) is monitored by chromatography or by GC-MS, preferably by HPLC chromatography especially with a UV detector, in particular the progress of the formation of the compound of formula (IV) as well as also its geometric isomers and of its salts with organic or inorganic bases, preferably inorganic bases.

[0131] As indicated above, the process according to the invention comprises:

[0132] - at least one step (i) as described above, such that at least one precipitate is formed, the at least one precipitate comprising at least the compound of formula (IV), its geometric isomers and / or one of its salts with organic or inorganic bases, preferably inorganic bases,

[0133] - at least one step (i1) of separating the precipitate from the reaction medium of step (i), preferably by filtration, more preferably by pressure filtration, for example using a piston, and then

[0134] - at least one step (i2) of acidifying the precipitate with at least one inorganic or organic, preferably inorganic acidifying agent, followed by reaction step (ii).

[0135] Preferably, the separation step (i1) is carried out by filtration, more preferably by pressure filtration, centrifugal filtration, or by centrifugation.

[0136] Preferably, the acidifying agent in step (i2) is an inorganic acidifying agent, in particular an inorganic acidifying agent of the H + Hal - type, where Hal represents a halogen atom selected from the group consisting of chlorine, bromine, and iodine. More preferably, the acidifying agent is hydrochloric acid.

[0137] Preferably, once the reaction step (i) is completed, the reaction medium is cooled to a temperature below or equal to 25 °C, preferably in the temperature range from 1 °C to 12 °C, more preferably in the range from 3 °C to 8 °C, and then the precipitate is separated from the reaction medium, preferably by filtration, more preferably by pressure filtration.

[0138] In other words, once the reaction step (i) is completed, the reaction medium is preferably cooled to a temperature below or equal to 25 °C, preferably in the range from 1 °C to 12 °C, more preferably in the range from 3 °C to 8 °C, and then the separation step (i1) is carried out.

[0139] Once separated from the reaction medium, the precipitate can be washed one or more times with at least one aprotic organic solvent such as acetone, and then it can be washed one or more times with at least one protic polar solvent such as water.

[0140] Preferably, the acidification step (i2) includes:

[0141] - In particular, at least the precipitate, which can be in powder form, is introduced into the reactor,

[0142] ○ Preferably together with at least one polar protic solvent such as water and optionally at least one (non)polar aprotic organic solvent such as acetone, in particular in an amount ranging from 10% polar protic solvent and 90% (non)polar aprotic solvent (by volume) to 90% polar protic solvent and 10% (non)polar aprotic solvent (by volume), especially 50% polar protic solvent and 50% (non)polar aprotic solvent (by volume),

[0143] - At least one inorganic or organic, preferably inorganic acidifying agent is added to the reaction medium containing the precipitate, preferably until a homogeneous suspension is obtained in the solvent as defined above;

[0144] ○ Preferably, the acidifying agent is an inorganic acid, in particular hydrochloric acid,

[0145] ○ Preferably, the pH of the reaction medium in step (i2) is less than 7, more preferably varying from 1 to 6, even more preferably from 2 to 5, and even better less than 4,

[0146] ○ Preferably, the temperature of the reaction medium in step (i2) is maintained at a temperature below or equal to 25 °C, more preferably in the temperature range from 1 °C to 20 °C, even better from 3 °C to 20 °C.

[0147] ○ More preferably, during the addition of the acidifying agent, the reaction medium is maintained at a temperature below or equal to 25 °C, especially in the range from 5 °C to 25 °C, particularly from 15 °C to 20 °C.

[0148] ○ More preferably, after the addition of the acidifying agent, the reaction medium is maintained at a temperature below or equal to 15 °C, especially in the range from 1 °C to 15 °C, particularly from 2 °C to 10 °C, more particularly in the range from 3 °C to 8 °C.

[0149] Once step (i2) has been carried out, the precipitate is preferably filtered off and then optionally washed one or more times with at least one polar protic solvent such as water. Preferably, the precipitate is washed twice with at least one polar protic solvent such as water.

[0150] After steps (i1) and (i2) have been carried out, the compound of formula (IV) advantageously has a high purity, especially greater than or equal to 97%, as measured by HPLC.

[0151] After steps (i1) and (i2) have been carried out and before step (ii) is carried out, the compound of formula (IV) is preferably dissolved in at least one (non)polar aprotic organic solvent, optionally as a mixture with at least one polar protic solvent such as water, preferably at least one nonpolar aprotic organic solvent.

[0152] Preferably, the nonpolar aprotic organic solvent has a dielectric constant E in the range from 1 to 11 and a dipole moment μ in the range from 0 to 2, and may be selected from the group consisting of: n-hexane, cyclohexane, 1,4-dioxane, carbon tetrachloride (CCl4), benzene, tetrachloroethylene (Cl2C═Cl2C), toluene, carbon disulfide (CS2), trichloroethylene (Cl2C═CHCl), diethyl ether (Et2O), ethyl acetate (CH3C(O)OEt or AcOEt), dimethyl ether (DME), tetrahydrofuran (THF), methyltetrahydrofuran (2-MeTHF), dichloromethane (CH2Cl2), dichloroethane (ClCH2CH2Cl), and mixtures thereof.

[0153] When the compound of formula (IV) is dissolved in at least one (non)polar aprotic organic solvent, the pH of the reaction medium is preferably greater than 5.

[0154] The compound of formula (IV) can be dissolved in at least one (non)-polar aprotic organic solvent, preferably at least one non-polar aprotic organic solvent, optionally as a mixture with at least one polar protic solvent such as water, in the presence of at least one base agent, the at least one base agent having a pKa varying from 8 to 11, preferably from 9 to 11, and being particularly selected from the group consisting of alkali metal carbonates (hydrogencarbonates) or alkaline earth metal carbonates (hydrogencarbonates).

[0155] Preferably, when dissolving the compound of formula (IV) in at least one (non)-polar aprotic organic solvent:

[0156] - The reaction medium is heated to a temperature above or equal to 40 °C, in particular to a temperature of 45 °C, and then

[0157] - The reaction medium is cooled to a temperature below 25 °C, in particular to a temperature of 20 °C, and then

[0158] - The reaction medium is allowed to settle in order to then remove the aqueous phase,

[0159] - Then the resulting organic phase is washed one or more times with water, preferably at a temperature in the range from 15 °C to 25 °C, in particular at a temperature of 20 °C, and then allowed to stand and settle,

[0160] - Then water is removed, preferably by distillation using a Dean-Stark apparatus, in particular at a temperature above or equal to 80 °C, in particular at a temperature in the range from 80 °C to 90 °C, preferably from 82 °C to 85 °C. According to another variant, water can be removed using a Dean-Stark apparatus under vacuum at a temperature below 80 °C.

[0161] Advantageously, the method according to the invention comprises:

[0162] - At least one step (i) as described above, such that at least one precipitate is formed, the at least one precipitate comprising at least the compound of formula (IV), its geometric isomers and / or one of its salts with an organic or inorganic base, preferably an inorganic base,

[0163] - At least one step (i1) of separating the precipitate from the reaction medium of step (i), preferably by filtration, more preferably by pressure filtration, for example using a piston, and then

[0164] - At least one step (i2) of acidifying the precipitate using at least one inorganic or organic, preferably inorganic acidifying agent, followed by reaction step (ii), and then

[0165] - Before step (ii), at least one step of dissolving the compound of formula (IV) in at least one (non)polar aprotic organic solvent, preferably at least one nonpolar aprotic organic solvent as defined above.

[0166] As indicated above, the method according to the invention includes step (ii) of reducing the compound of formula (IV) to produce at least one compound of formula (I).

[0167] Step (ii) of reducing the compound of formula (IV) can be carried out in the presence or absence of at least one solvent.

[0168] Preferably, reduction step (ii) can be catalytic reduction, preferably reduction by catalytic hydrogenation, or reduction by conventional reducing agents known to those skilled in the art, such as alkali metal hydrides, for example alkali metal borohydrides such as NaBH4, and alkali metal aluminum tetrahydrides such as LiAlH4.

[0169] Preferably, reduction step (ii) is reduction by catalytic hydrogenation.

[0170] Advantageously, the compound of formula (IV) is dissolved in at least one (non)polar aprotic organic solvent, preferably at least one nonpolar aprotic organic solvent as defined above, and then hydrogenated to produce at least one compound of formula (I).

[0171] Preferably, step (ii) is hydrogenation carried out in the presence of at least one catalyst.

[0172] The catalyst is preferably palladium (Pd), such as palladium on carbon (Pd / C), palladium on aluminum (Pd / Al), palladium AlSi or palladium barium sulfate (BaSO4), ruthenium (Ru) or nickel (Ni), more particularly selected from Pd and Ru.

[0173] Preferably, the catalyst is palladium (Pd), such as palladium on carbon (Pd / C).

[0174] Preferably, the catalyst is present in the reaction medium of step (ii) in an amount ranging from 0.05% to 10%, preferably from 0.1% to 10% by weight, preferably from 0.5% to 1% by weight, based on the total weight of the reaction medium of step (ii).

[0175] Preferably, step (ii) is hydrogenation carried out in the presence of at least one catalyst, preferably palladium (Pd) such as palladium on carbon (Pd / C), particularly in the presence of at least one base agent having a pKa ranging from 8 to 11, preferably from 9 to 11, especially from 9 to 10, preferably selected from the group consisting of alkali metal carbonates (hydrogencarbonates) or alkaline earth metal carbonates (hydrogencarbonates) and mixtures thereof.

[0176] As a variant, the basic agent having a pKa in the range from 8 to 11, preferably from 9 to 11, in particular from 9 to 10, can be introduced into the reaction medium comprising at least the compound of formula (IV) before carrying out the reduction step (ii), in particular when the compound of formula (IV) is dissolved in at least one (non)polar aprotic organic solvent as described above.

[0177] Preferably, the reduction step (ii) is carried out in a reaction medium having a pH varying from 8 to 11, preferably from 9 to 10, which makes it possible to further limit the formation of impurities.

[0178] Preferably, the reduction step (ii) is carried out at a temperature of greater than or equal to 20 °C, more preferably greater than or equal to 50 °C, even more preferably greater than or equal to 80 °C. According to a preferred embodiment, the temperature is in the range between 20 °C and 150 °C, more particularly in the range between 30 °C and 100 °C, preferably in the range between 50 °C and 80 °C.

[0179] At the end of the reaction step (ii), the reaction medium is preferably cooled to a temperature of less than or equal to 45 °C, after which the catalyst can optionally be filtered out.

[0180] The reaction medium can be rinsed with at least one nonpolar aprotic organic solvent such as methyl-THF.

[0181] Preferably, at the end of the reaction step (ii), the reaction medium comprising the compound of formula (I) can be washed by one or more acid-base washing operations, in particular by successively adding at least one organic or inorganic, preferably inorganic basic agent and at least one organic or inorganic, preferably inorganic acidifying agent.

[0182] By way of example, preferably:

[0183] - at least one basic agent (preferably selected from the group consisting of alkali metal hydroxides or alkaline earth metal hydroxides, in particular sodium hydroxide) and at least one polar protic solvent such as water are added to the reaction medium comprising the compound of formula (I),

[0184] - the reaction medium is allowed to settle, and then the aqueous phase is removed from the reaction medium,

[0185] - the resulting organic phase is then washed one or more times with water, and then the water is removed,

[0186] - at least one, preferably inorganic acidifying agent and water are added to the resulting organic phase; the resulting reaction medium particularly has a pH of less than 2,

[0187] - then the aqueous phase is removed,

[0188] - Wash the resulting organic phase one or more times with water and then remove the non-polar aprotic organic solvents that may be present in the organic phase by vacuum distillation, particularly at a temperature in the range from 75 °C to 85 °C.

[0189] At the end of step (ii), preferably after one or more acid-base washing steps, the compound of formula (I) is advantageously purified by distillation, preferably short-path distillation, in order to remove any residual volatile or non-volatile impurities.

[0190] The compound of formula (I) can then be isolated in a yield of at least 90% and a purity of at least 95%.

[0191] As indicated above, the process according to the invention is a process for preparing at least one compound of formula (I) as defined above, one of its optical or geometric isomers, and / or one of its salts with an organic or inorganic acid or base, and / or one of its solvates such as a hydrate.

[0192] The salts of the compound of formula (I) include the conventional non-toxic salts of said compound, such as those formed by an acid or a base.

[0193] As salts of the compound of formula (I), mention may be made in particular of:

[0194] - salts obtained by adding an inorganic base to the compound of formula (I), the inorganic base being, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, magnesium hydroxide, lithium hydroxide, and sodium carbonate, potassium carbonate, or calcium carbonate, or sodium bicarbonate, potassium bicarbonate, or calcium bicarbonate;

[0195] - salts obtained by adding an organic base to the compound of formula (I), the organic base being, for example, a primary, secondary or tertiary alkylamine, such as triethylamine or butylamine. Such a primary, secondary or tertiary alkylamine may contain one or more nitrogen and / or oxygen atoms and may thus contain, for example, one or more alcohol functional groups; mention may be made in particular of 2-amino-2-methylpropanol, ethanolamine, triethanolamine, 2-(dimethylamino)propanol, 2-amino-2-hydroxymethyl-1,3-propanediol or 3-(dimethylamino)propylamine.

[0196] Also mention may be made of salts of amino acids such as lysine, arginine, guanidine, glutamic acid or aspartic acid.

[0197] Advantageously, the salts of the compound of formula (I) may be selected from alkali metal salts or alkaline earth metal salts, such as sodium salts, potassium salts, calcium salts or magnesium salts, or ammonium salts.

[0198] The acceptable solvates of the compound of formula (I) include the conventional solvates, such as those formed during the preparation of said compound due to the presence of a solvent.

[0199] Examples that may be mentioned include solvates formed due to the presence of water or linear or branched alcohols such as ethanol or isopropanol.

[0200] Optical isomers are in particular enantiomers and diastereomers.

[0201] Preferably, in formula (I), R 2 represents a hydrogen atom.

[0202] Preferably, in formula (I), R 1 represents a linear or branched, preferably linear C1-C4 alkyl group, more preferably a linear C2-C4 alkyl group such as ethyl.

[0203] Preferably, in formula (I), R 3 represents a linear or branched C1-C6 alkyl group optionally substituted with an aryl group as described above.

[0204] Preferably, in formula (I), R 2 represents a hydrogen atom and / or R 1 represents a linear or branched, preferably linear C1-C4 alkyl group, more preferably a linear C2-C4 alkyl group such as ethyl and / or R 3 represents a linear or branched C1-C6 alkyl group.

[0205] More preferably, the method according to the invention is a method for preparing at least one compound of formula (I):

[0206]

[0207] In formula (I):

[0208] -R 1 represents a linear or branched, preferably linear C1-C4 alkyl group, more preferably a linear C2-C4 alkyl group such as ethyl;

[0209] -R 2 represents a hydrogen atom;

[0210] -R 3 represents a linear or branched, saturated or unsaturated hydrocarbon group containing 1 to 12 atoms optionally substituted with an aryl group; the aryl group is preferably a phenyl group optionally substituted with one or more groups selected from hydroxy, C1-C4 alkyl, C1-C4 alkoxy and combinations thereof; preferably, R 3 represents a linear or branched C1-C6 alkyl group; preferably a linear or branched C1-C4 alkyl group such as methyl or ethyl;

[0211] Preferably, in formula (I), R 1 represents a linear or branched C2-C4 alkyl group, especially ethyl, R 2 represents a hydrogen atom, R 3represents a C1-C6 alkyl group; preferably a C1-C4 alkyl group, especially a methyl group.

[0212] In other words, even more preferably, the process according to the invention is a process for preparing at least one compound of formula (I):

[0213]

[0214] In formula (I):

[0215] -R 1 represents a straight-chain or branched C2-C4 alkyl group, especially an ethyl group;

[0216] -R 2 represents a hydrogen atom;

[0217] -R 3 represents a straight-chain or branched C1-C6 alkyl group; preferably a C1-C4 alkyl group, especially a methyl group.

[0218] Advantageously, the process according to the invention makes it possible to prepare one or more compounds of formula (I) selected from the group consisting of compounds corresponding to formula (I”):

[0219]

[0220] as well as their optical isomers, geometric isomers and tautomers, as well as their salts with organic or inorganic acids or bases, and their solvates such as hydrates.

[0221] Preferably, the process according to the invention makes it possible to prepare one or more compounds of formula (I) selected from the group consisting of compounds corresponding to formula (I’):

[0222]

[0223] In formula (I’):

[0224] -R 1 represents a straight-chain or branched, saturated or unsaturated hydrocarbon group containing 1 to 6 carbon atoms; preferably, R 1 represents a C1-C4 alkyl group, more preferably a C2-C4 alkyl group such as an ethyl group;

[0225] -R 2 represents a hydrogen atom or a C2-C4 alkyl group such as a methyl or ethyl group;

[0226] -R 3 represents a branched, saturated or unsaturated hydrocarbon group containing 1 to 12 carbon atoms, preferably R 3 represents a branched, saturated or unsaturated hydrocarbon group containing 3 to 12 carbon atoms; more preferably R 3represents a branched C1-C6 alkyl group, more preferably R 3 represents a branched C3-C6 alkyl group; in particular R 3 represents a branched C3-C4 alkyl group, especially a branched C4 alkyl group;

[0227] and also one of its optical or geometric isomers, and / or one of its salts with an organic or inorganic acid or base, and / or one of its solvates such as a hydrate.

[0228] Thus, the process according to the invention makes it possible, preferably, to prepare the compound of formula (I') according to the following synthesis scheme (1"):

[0229]

[0230] ■ In the synthesis route (1"):

[0231] -R 1 、R 2 and R 3 have the same meanings as those indicated in formula (I');

[0232] More preferably, the process makes it possible to prepare the compound of formula (I") from ethyl vanillin (II'a) according to the following synthesis scheme (1'''):

[0233]

[0234] The process according to the invention for preparing the compound of formula (I') or (I") comprises at least one step (i) as defined above, at least one separation step (i1) and at least one acidification step (i2).

[0235] The process according to the invention for preparing the compound of formula (I') or (I") comprises at least one reduction step (ii) as described above.

[0236] Preferably, the process according to the invention for preparing the compound of formula (I') or (I") comprises the step of dissolving the compound of formula (IV) or (IV'a) as described above.

[0237] Preferably, the process according to the invention for preparing the compound of formula (I') or (I") comprises, at the end of step (ii), one or more acid-base washing steps and / or at least one purification step, preferably short-path distillation, in order to remove any residual volatile or non-volatile impurities.

[0238] Compound of formula (I’)

[0239] As indicated above, the invention also relates to a compound of the following formula (I'):

[0240]

[0241] In formula (I'):

[0242] -R 1 represents a straight-chain or branched-chain, saturated or unsaturated hydrocarbon group having 1 to 6 carbon atoms; preferably, R 1 represents a C1-C4 alkyl group, more preferably a C2-C4 alkyl group such as ethyl;

[0243] -R 2 represents a hydrogen atom or a C2-C4 alkyl group such as methyl or ethyl; preferably, R 2 represents a hydrogen atom;

[0244] -R 3 represents a branched-chain, saturated or unsaturated hydrocarbon group having 1 to 12 atoms; preferably, R 3 represents a branched-chain, saturated or unsaturated hydrocarbon group having 3 to 12 carbon atoms; more preferably, R 3 represents a branched-chain C1-C6 alkyl group, more preferably, R 3 represents a branched-chain C3-C6 alkyl group; in particular, R 3 represents a branched-chain C3-C4 alkyl group, especially a branched-chain C4 alkyl group;

[0245] and also one of its optical isomers or geometric isomers, and / or one of its salts with an organic or inorganic acid or base, and / or one of its solvates such as a hydrate.

[0246] Preferably, in formula (I'), R 3 represents a branched-chain C1-C6 alkyl group, more preferably, R 3 represents a branched-chain C1-C4 alkyl group, especially a branched-chain C4 alkyl group.

[0247] Preferably, in formula (I'), R 3 represents a branched-chain C1-C6 alkyl group, more preferably, R 3 represents a branched-chain C3-C6 alkyl group, especially a branched-chain C1-C4 alkyl group, even more preferably, R 3 represents a branched-chain C3-C4 alkyl group, especially a branched-chain C4 alkyl group.

[0248] According to a preferred embodiment, in formula (I'), R 3 represents a branched-chain C3-C6 alkyl group; in particular, R 3 represents a branched-chain C3-C4 alkyl group, especially a branched-chain C4 alkyl group.

[0249] Preferably, in formula (I'), R 2 represents a hydrogen atom.

[0250] Preferably, in formula (I'), R1 represents a C1-C4 alkyl group, more preferably a C2-C4 alkyl group such as ethyl.

[0251] Furthermore, the present invention also relates to a composition which comprises at least one compound of formula (I’), its salt and / or isomer and / or solvate as described above.

[0252] Preferably, the composition comprises at least one compound of formula (I’), its salt and / or isomer and / or solvate in an amount greater than 10% by weight relative to the total weight of the composition.

[0253] Compound of formula (I)

[0254] Another subject of the present invention is a compound of formula (I) or (I’), preferably (I”), and / or one of its salts and / or one of its geometric or optical isomers and / or one of its solvates obtained by the method according to the invention as defined above.

[0255] Composition comprising a compound of formula (I) or (I’)

[0256] Another subject of the present invention is a composition which comprises at least one compound of formula (I) or (I’), preferably (I”), and / or one of its salts with an organic or inorganic acid or base and / or one of its geometric or optical isomers and / or one of its solvates such as a hydrate obtained by the method according to the invention as described above.

[0257] Preferably, the composition comprises at least one compound of formula (I) or (I’), preferably (I”), and / or one of its salts and / or one of its geometric or optical isomers and / or one of its solvates in an amount greater than 10% by weight relative to the total weight of the composition.

[0258] For the purposes of the present invention, “an amount or content greater than 10% by weight” should be understood to mean that the compound of formula (I) or (I’) is present in an amount or content strictly greater than 10% by weight relative to the total weight of the composition, that is to say excluding the value of 10% by weight.

[0259] If the composition of the present invention comprises several different compounds of formula (I) or (I’), “an amount or content greater than 10% by weight” should be understood to mean that the sum by weight of the compounds of formula (I) or (I’) relative to the total weight of the composition is strictly greater than 10% by weight, that is to say excluding the value of 10% by weight.

[0260] Preferably, the compound of formula (I) or (I') obtained according to the method as defined above is present in an amount of greater than or equal to 20% by weight, more preferably greater than or equal to 30% by weight, even more preferably greater than or equal to 40% by weight, still better greater than or equal to 50% by weight, even still better greater than or equal to 60% by weight, particularly greater than or equal to 70% by weight, more particularly greater than or equal to 80% by weight, especially greater than or equal to 90% by weight, based on the total weight of the composition according to the invention.

[0261] Preferably, the compound of formula (I") obtained according to the method as defined above is present in an amount of greater than or equal to 20% by weight, more preferably greater than or equal to 30% by weight, even more preferably greater than or equal to 40% by weight, still better greater than or equal to 50% by weight, even still better greater than or equal to 60% by weight, particularly greater than or equal to 70% by weight, more particularly greater than or equal to 80% by weight, especially greater than or equal to 90% by weight, based on the total weight of the composition according to the invention.

[0262] Preferably, the compound of formula (I) or (I') obtained according to the method as defined above is present in an amount ranging from 30% to 99% by weight, more preferably from 50% to 98% by weight, even more preferably from 60% to 97% by weight, still better from 70% to 96% by weight, even still better from 75% to 95% by weight, particularly from 80% to 94% by weight, more particularly from 85% to 93% by weight, such as 90% by weight, based on the total weight of the composition.

[0263] Preferably, the compound of formula (I") obtained according to the method as defined above is present in an amount ranging from 30% to 99% by weight, more preferably from 50% to 98% by weight, even more preferably from 60% to 97% by weight, still better from 70% to 96% by weight, even still better from 75% to 95% by weight, particularly from 80% to 94% by weight, more particularly from 85% to 93% by weight, such as 90% by weight, based on the total weight of the composition.

[0264] Advantageously, the compound of formula (I) or (I') obtained according to the method as defined above, preferably the compound of formula (I''), is present in the composition in an amount ranging from 75% to 95% by weight, in particular from 80% to 94% by weight, more particularly from 85% to 93% by weight, such as 90% by weight, based on the total weight of the composition.

[0265] Advantageously, the compound of formula (I'') obtained according to the method as defined above is present in the composition in an amount ranging from 75% to 95% by weight, in particular from 80% to 94% by weight, more particularly from 85% to 93% by weight, such as 90% by weight, based on the total weight of the composition.

[0266] Preferably, the composition further comprises at least one (non)-polar (non)-protic organic solvent, preferably a polar protic organic solvent.

[0267] Preferably, the (non)-polar (non)-protic organic solvent is selected from polar protic organic solvents such as polyols.

[0268] The term "(poly)ol" should be understood to mean a compound that is liquid at room temperature (25 °C) and atmospheric pressure (1.013×10 5 Pa) and that contains a hydrocarbon chain of C2 to C 10 , in particular C2 to C5, more particularly C3 to C4, such as C3, which is straight-chain or branched, saturated or unsaturated, preferably saturated and contains one or more hydroxyl groups, preferably 2 to 5 hydroxyl groups, more particularly 2 to 3, more preferably 2 hydroxyl groups.

[0269] Preferably, the (poly)ol is selected from (C2-C 10 ) alkane (poly)ols, more preferably from (C2-C6) alkane (poly)ols.

[0270] For the purposes of the present invention, the term "(C2-C 10 ) alkane (poly)ol" should be understood to mean a straight-chain or branched, preferably straight-chain alkane that contains from 1 to 10 carbon atoms and contains one or more hydroxyl groups (-OH), preferably 2 or 3 hydroxyl groups, more preferably 2 hydroxyl groups.

[0271] In particular, the (non)-polar (non)-protic organic solvent is a (C2-C6) alkanediol or a (C2-C6) alkanetriol, preferably a (C2-C6) alkanediol. More preferably, the (non)-polar (non)-protic organic solvent is a (C2-C4) alkanediol or a (C2-C4) alkanetriol, preferably a (C2-C4) alkanediol.

[0272] Preferably, the (non)-polar (aprotic) organic solvent is a propylene glycol, especially selected from the group consisting of propane-1,2-diol (or propylene glycol), propane-1,3-diol, butane-1,3-diol (or butylene glycol), and mixtures thereof, preferably 1,3-propanediol.

[0273] According to a specific embodiment of the invention, the composition comprises one or more (C2-C6) alkanols, preferably (C2-C4) alkanols such as ethanol, as the (non)-polar (aprotic) organic solvent.

[0274] According to a specific embodiment of the invention, the composition comprises a mixture of (non)-polar (aprotic) organic solvents that are different from each other, especially a mixture of one or two (C2-C6) alkanediols, preferably two (C2-C4) alkanediols and a (C2-C6) alkanol, preferably a (C2-C4) alkanol such as ethanol.

[0275] According to another specific embodiment of the invention, the composition comprises a mixture of the following (non)-polar (aprotic) organic solvents that are different from each other: two or more (C2-C6) alkanediols, preferably two (C2-C4) alkanediols.

[0276] Preferably, the (non)-polar (aprotic) organic solvent can be present in an amount of greater than or equal to 1% by weight, especially in an amount of greater than or equal to 9% by weight, more especially in an amount between 2% and 75% by weight, even more especially in an amount between 3% and 50% by weight, preferably in an amount ranging from 3% to 20% by weight, more preferably in an amount ranging from 5% to 15%, such as 9% by weight, based on the total weight of the composition.

[0277] According to an embodiment of the invention, the composition further comprises ii) at least one (non)-polar (aprotic) organic solvent such as at least one polyol as defined above, in an amount of less than or equal to 70% by weight, especially in an amount of less than or equal to 50% by weight, preferably in an amount of less than or equal to 20% by weight, preferably in an amount between 1% and 15% by weight, more preferably between 5% and 12%, such as 9% by weight, based on the total weight of the composition.

[0278] Advantageously, the composition comprises i) at least one compound of formula (I) or (I’), preferably formula (I”), obtained by the method according to the invention, in an amount of greater than 10% by weight based on the total weight of the composition; and ii) at least one polar protic organic solvent, preferably at least one (C2-C6) alkane (poly)ol.

[0279] Advantageously, the composition comprises at least one compound of formula (I) or (I’), preferably of formula (I”), obtained by the process according to the invention, in an amount greater than 10% by weight relative to the total weight of the composition; and at least one (C2-C6) alkane polyol, preferably at least one (C2-C6) alkanediol.

[0280] Advantageously, the composition comprises one or more compounds of formula (I) or (I’), preferably of formula (I”), obtained by the process according to the invention, in a content of more than 10% by weight; and at least one polar protic organic solvent selected from the group consisting of propane-1,2-diol, propane-1,3-diol, and mixtures thereof, more preferably 1,3-propanediol.

[0281] Preferably:

[0282] - The compound of formula (I) or (I’), preferably of formula (I”), obtained by the process according to the invention is present in a content ranging from 30% to 99% by weight, more preferably from 50% to 98% by weight, even more preferably from 60% to 97% by weight, still better from 70% to 96% by weight, even still better from 75% to 95% by weight, especially from 80% to 94% by weight, more particularly from 85% to 93% by weight, such as 90% by weight, relative to the total weight of the composition, and

[0283] - The (non)-polar (aprotic) organic solvent, preferably the polar protic organic solvent, is present in an amount of at least 1% by weight, particularly at least 9% by weight, more particularly between 2% and 75% by weight, even more particularly between 3% and 50% by weight, preferably in a range from 3% to 20% by weight, more preferably in a range from 5% to 15% by weight, such as 9% by weight, relative to the total weight of the composition.

[0284] Preferably:

[0285] - The compound of formula (I) or (I’), preferably of formula (I”), obtained by the process according to the invention is present in a content ranging from 30% to 99% by weight, more preferably from 50% to 98% by weight, even more preferably from 60% to 97% by weight, still better from 70% to 96% by weight, even still better from 75% to 95% by weight, especially from 80% to 94% by weight, more particularly from 85% to 93% by weight, such as 90% by weight, relative to the total weight of the composition, and

[0286] -(Non)-polar (non)-protic organic solvents, preferably polar protic organic solvents, are present in an amount of less than or equal to 70% by weight, particularly less than or equal to 50% by weight, preferably less than or equal to 20% by weight, preferably in an amount between 1% and 15% by weight, more preferably between 5% and 12% by weight, such as 9% by weight, based on the total weight of the composition.

[0287] Preferably, the composition according to the invention comprises at least one compound of formula (I) or (I'), preferably of formula (I''), and / or one of its salts and / or one of its geometric or optical isomers and / or one of its solvates obtained by the method according to the invention as defined above; at least one (non)-polar (non)-protic organic solvent, preferably a polar protic organic solvent; and optionally water, preferably water.

[0288] Preferably, the composition according to the invention comprises at least one compound of formula (I) or (I'), preferably of formula (I''), and / or one of its salts and / or one of its geometric or optical isomers and / or one of its solvates; at least one (non)-polar (non)-protic organic solvent, preferably a polar protic organic solvent; and optionally water, preferably water.

[0289] Preferably, water can be present in an amount of less than or equal to 20% by weight, preferably less than or equal to 10% by weight, more preferably in a range from 0.05% to 5% by weight, even more preferably in a range from 0.5% to 3% by weight, still better in a range from 0.8% to 1.5% by weight, such as 1% by weight, based on the total weight of the composition.

[0290] Advantageously, the composition according to the invention comprises at least one compound of formula (I) or (I'), preferably of formula (I''), obtained by the method according to the invention, in an amount greater than 10% by weight based on the total weight of the composition; at least one (non)-polar (non)-protic organic solvent, preferably a polar protic organic solvent, in an amount greater than or equal to 1% by weight based on the total weight of the composition; and water, in an amount less than or equal to 20% by weight based on the total weight of the composition.

[0291] Advantageously,

[0292] - The compound of formula (I) or (I'), preferably of formula (I''), obtained by the method as described above is present in a range from 75% to 95% by weight based on the total weight of the composition,

[0293] -(Non)-polar (non)-protic organic solvents, preferably polar protic organic solvents, are present in a range from 5% to 20% by weight based on the total weight of the composition,

[0294] - Water may be present in an amount ranging from 0.05% to 5% by weight, based on the total weight of the composition.

[0295] Advantageously,

[0296] - The compound of formula (I) or (I’), preferably formula (I”), is present in an amount ranging from 75% to 95% by weight, based on the total weight of the composition.

[0297] - The (non)polar (aprotic) organic solvent, preferably the polar protic organic solvent, is present in an amount ranging from 5% to 20% by weight, based on the total weight of the composition.

[0298] - Water may be present in an amount ranging from 0.05% to 5% by weight, based on the total weight of the composition.

[0299] More advantageously, the composition consists of:

[0300] i) The compound of formula (I) or (I’), preferably formula (I”), obtained according to the method as defined above, in an amount of 75% to 95% by weight, based on the total weight of the composition.

[0301] ii) The (non)polar (aprotic) organic solvent, preferably the polar protic organic solvent, in an amount of 5% to 20% by weight, based on the total weight of the composition, and

[0302] iii) Water in an amount of 0.05% to 5% by weight, based on the total weight of the composition.

[0303] More advantageously, the composition consists of:

[0304] i) The compound of formula (I) or (I’), preferably formula (I”), in an amount of 75% to 95% by weight, based on the total weight of the composition.

[0305] ii) The (non)polar (aprotic) organic solvent, preferably the polar protic organic solvent, in an amount of 5% to 20% by weight, based on the total weight of the composition, and

[0306] iii) Water in an amount of 0.05% to 5% by weight, based on the total weight of the composition.

[0307] Even more preferably, the composition of the present invention consists of:

[0308] i) The compound of formula (I) or (I’), preferably formula (I”), obtained according to the method as defined above, in an amount of 75% to 95% by weight, based on the total weight of the composition.

[0309] ii) from 5% to 20% by weight, relative to the total weight of the composition, of a (non)-polar (non)-protic organic solvent, preferably a polar protic organic solvent, preferably a (C2-C6) alkanediol, more preferably selected from propan-1,2-diol, propan-1,3-diol and mixtures thereof, even more preferably 1,3-propanediol, and

[0310] iii) from 0.05% to 5% by weight, relative to the total weight of the composition, of water.

[0311] Even better, the composition of the invention consists of:

[0312] i) from 75% to 95% by weight, relative to the total weight of the composition, of a compound of formula (I) or (I’), preferably of formula (I”);

[0313] ii) from 5% to 20% by weight, relative to the total weight of the composition, of a (non)-polar (non)-protic organic solvent, preferably a polar protic organic solvent, preferably a (C2-C6) alkanediol, more preferably selected from propan-1,2-diol, propan-1,3-diol and mixtures thereof, even more preferably 1,3-propanediol, and

[0314] iii) from 0.05% to 5% by weight, relative to the total weight of the composition, of water.

[0315] According to a preferred embodiment of the invention, the composition consists of: i) 90% + / - 5% by weight of a compound of formula (I) or (I’), preferably of formula (I”), obtained according to the method of the invention as described above; ii) 9% + / - 2% by weight of a polar protic organic solvent, in particular a polyol, preferably a (C2-C6) alkanediol, more preferably selected from the group consisting of propan-1,2-diol, propan-1,3-diol, butanediol and mixtures thereof, even more preferably 1,3-propanediol; and 1% + / - 0.5% by weight of water, provided that the sum of components i) + ii) + iii) is equal to 100%.

[0316] According to a preferred embodiment of the invention, the composition consists of: i) 90% + / - 5% by weight of a compound of formula (I) or (I’), preferably of formula (I”); ii) 9% + / - 2% by weight of a polar protic organic solvent, in particular a polyol, preferably a (C2-C6) alkanediol, more preferably selected from the group consisting of propan-1,2-diol, propan-1,3-diol, butanediol and mixtures thereof, even more preferably 1,3-propanediol; and 1% + / - 0.5% by weight of water, provided that the sum of components i) + ii) + iii) is equal to 100%.

[0317] According to a preferred embodiment of the present invention, the composition consists of: i) 90% + / - 5% by weight of a compound of formula (I) or (I'), preferably formula (I''), obtained by the method as defined above; ii) 9% + / - 2% by weight of a polar protic organic solvent, in particular a polyol, preferably a (C2-C6) alkanediol, more preferably selected from the group consisting of propane-1,2-diol, propane-1,3-diol, butanediol and mixtures thereof, even more preferably 1,3-propanediol; and 1% + / - 0.5% by weight of water, provided that the sum of components i) + ii) + iii) is equal to 100%.

[0318] According to a preferred embodiment of the present invention, the composition consists of: i) 90% + / - 5% by weight of a compound of formula (I) or (I'), preferably formula (I''); ii) 9% + / - 2% by weight of a polar protic organic solvent, in particular a polyol, preferably a (C2-C6) alkanediol, more preferably selected from the group consisting of propane-1,2-diol, propane-1,3-diol, butanediol and mixtures thereof, even more preferably 1,3-propanediol; and 1% + / - 0.5% by weight of water, provided that the sum of components i) + ii) + iii) is equal to 100%.

[0319] According to a more preferred embodiment of the present invention, the composition consists of: relative to the total weight of the composition, i) 90% by weight of a compound of formula (I'') obtained by the method as defined above, ii) 9% by weight of 1,3-propanediol (as a substance that is liquid at room temperature and atmospheric pressure), and 1% by weight of water.

[0320] According to a more preferred embodiment of the present invention, the composition consists of: relative to the total weight of the composition, i) 90% by weight of a compound of formula (I''), ii) 9% by weight of 1,3-propanediol, and 1% by weight of water.

[0321] Compound of formula (IV’)

[0322] The present invention also relates to at least one compound of the following formula (IV'), its reduced form (IV' reduced), and also one of its optical isomers or Z / Z, Z / E, E / Z and E / E geometric isomers, and / or one of its salts with an organic or inorganic acid or base, and / or one of its solvates such as a hydrate:

[0323]

[0324] In formula (IV'):

[0325] -R 1 represents a straight-chain or branched-chain, saturated or unsaturated hydrocarbon group containing 1 to 6 carbon atoms; preferably, R1 represents a C1-C4 alkyl group, more preferably a C2-C4 alkyl group such as ethyl;

[0326] -R 2 represents a hydrogen atom or a C2-C4 alkyl group such as methyl or ethyl; preferably, R 2 represents a hydrogen atom.

[0327] Preferably, R 1 represents a straight-chain or branched-chain, saturated or unsaturated hydrocarbon group containing 2 to 6 carbon atoms.

[0328] Preferably, R 1 represents a C2-C4 alkyl group and R 2 represents a hydrogen atom or a C2-C4 alkyl group such as ethyl; preferably, R 2 represents a hydrogen atom.

[0329] Preferably, when the compound (IV') contains R representing ethyl 1 and R representing a hydrogen atom 2 then the compound (IV') is in the form of a salt of an inorganic base.

[0330] The reduced form of (IV') should be understood to mean a compound of the following formula (IV'reduced), one of its salts with an organic or inorganic acid or base, and / or one of its solvates such as a hydrate:

[0331]

[0332] Preferably, R 1 represents a straight-chain or branched-chain, saturated or unsaturated hydrocarbon group containing 2 to 6 carbon atoms.

[0333] Preferably, R 1 represents a C2-C4 alkyl group and R 2 represents a hydrogen atom or a C2-C4 alkyl group such as ethyl; preferably, R 2 represents a hydrogen atom.

[0334] Preferably, in formula (IV'), R 1 represents a C1-C4 alkyl group, more preferably a C2-C4 alkyl group such as ethyl, R 2 represents a hydrogen atom.

[0335] Furthermore, the present invention also relates to a composition comprising at least one compound of formula (IV'), its reduced form (IV'reduced), and also one of its optical isomers or Z / Z, Z / E, E / Z, and E / E geometric isomers, and / or one of its salts with an organic or inorganic acid or base, and / or one of its solvates such as a hydrate.

[0336] The compounds of formula (I), (I’), (I”) or (IV’) as defined above can be particularly used in compositions comprising a physiologically acceptable medium.

[0337] The physiologically acceptable medium in which the compounds of formula (I), (I’), (I”) or (IV’) can be used can be selected by those skilled in the art based on their common general knowledge according to the type of composition desired.

[0338] The present invention is illustrated in more detail in the following non-limiting examples.

[0339] Example 1:

[0340] Step 1: Preparation of the compound of formula (IV)

[0341]

[0342] At a temperature of 20 °C, ethyl vanillin (300 g, 1.81 mol) and then water (1140 ml, 3.8 V) are introduced into the reactor. The suspension is stirred and then acetone (600 ml, 2 V) is charged. The medium is cooled to 15 °C and then a 50% sodium hydroxide solution (400 ml, 7.6 mol) is added over 1 hour while not exceeding 25 °C. The medium is then heated at 30 °C for 12 h. It turns red and a phenolate precipitate forms. The suspension is cooled to a temperature of 5 °C and then filtered under pressure. The filter cake is washed with acetone (578 ml, 1.9 V) at 5 °C and then with water (227 ml, 0.8 V). In the presence of water (1755 ml, 5.9 V) and acetone (672 ml, 2.2 V), the wet solid is recharged into the reactor. 33% hydrochloric acid is added to this suspension at a temperature of 20 °C over 1 hour while maintaining the temperature of the medium at 15 °C. A mixture of previously prepared hydrochloric acid (115 ml, 1.23 mol), water (130 ml, 0.43 V) and acetone (48 ml, 0.16 V) is added to the resulting solution.

[0343] The pH is preferably less than 4. The suspension is stirred at a temperature of 25 °C for two hours and then cooled to a temperature of 5 °C, after which it is filtered under pressure.

[0344] The filter cake is washed twice with water (2 × 377 ml, 2 × 1.3 V) and then centrifuged until a solid content of > 35% is obtained. The yield is approximately 90% and a product with an HPLC titre > 97% is provided.

[0345] Step of dissolving the compound of formula (IV)

[0346] The water-wetted filter cake (770 g, 1.57 mol) is introduced into the reactor together with methyl-THF (1041 ml, 1.35 V) and water (74 ml, 0.1 V). A two-phase solution is obtained. The pH is preferably greater than 5.

[0347] The two-phase solution is heated to a temperature of 45 °C and then cooled to a temperature of 20 °C. After that, the mixture is decanted and the aqueous phase is drawn off. The organic phase is washed again with water (148 ml, 0.2 V) at 20 °C, then it is decanted, and water is removed by distillation using a Dean-Stark apparatus at 82 °C - 85 °C. Then the medium is concentrated to a solids content of 20% - 28%. The dry estimated yield is greater than 95% and the HPLC purity is greater than 97%.

[0348] Step 2: Catalytic hydrogenation to obtain the compound of formula (I’)

[0349]

[0350] The methyl-THF solution (1199 ml, 1.57 mol) is introduced into the hydrogenator together with 5% palladium on carbon containing 50% water (1.62 g, 0.14% w / w) and sodium bicarbonate.

[0351] Then hydrogen is introduced and the reaction medium is heated to a temperature in the range from 100 °C to 150 °C. The hydrogenation reaction is carried out until all the hydrogen has been consumed.

[0352] Then the reaction medium is cooled to a temperature of 40 °C, after which the catalyst is filtered out. The reactor and the catalyst are rinsed with methyl-THF (100 ml, 0.1 V). The filtrate is added to the first filtrate for purification. The dry estimated yield is greater than 95% and the HPLC purity is greater than 95%.

[0353] Acid-base washing step

[0354] At a temperature of 20 °C, a solution containing the compound of formula (I) obtained during the catalytic hydrogenation step (2697 g, 2.98 mol), water (85 ml, 0.03 V) and sodium hydroxide (1.9 ml) is introduced into the reactor to a pH of 12.

[0355] The reaction medium is stirred for a period of 10 minutes, after which the aqueous phase is drawn off. The organic phase is washed again with water (85 ml) and then it is decanted.

[0356] Check the content of ethyl vanillin in the organic phase (≤0.4% HPLC), and then add water (85 ml) and 33% hydrochloric acid (1.2 ml) to pH 1.5 - 2. Stir the medium for 10 minutes, after which the aqueous phase is drawn off. Then the organic phase is washed again with water (85 ml), then decanted and drawn off, and then methyl - THF is removed by distillation at 80 °C under vacuum until a solids content of at least 97% is reached. The crude product is isolated in the form of a thick honey at 50 °C with a purity of approximately 98% in a 90% yield.

[0357] Short-path distillation step

[0358] At the end of the acid - base washing step, the compound of formula (I) is melted and loaded into the feed tank of a distillation apparatus at 50 °C and introduced into a short - path distillation apparatus at a constant flow rate.

[0359] The crude product is isolated in the form of a thick honey at 50 °C with a purity of approximately 98% in a 90% yield.

[0360] Dilution step

[0361] The pre - melted compound of formula (I) is loaded into a reactor at 50 °C together with a polar protic organic solvent, preferably a (C1 - C6) alkane (poly)ol and water.

[0362] After stirring at 50 °C for 30 minutes, the product is encapsulated in a 100% yield.

[0363] Example 2:

[0364] Step 1: Preparation of the compound of formula (IV’a) and its salts with inorganic bases (sodium hydroxide).

[0365]

[0366] Ethyl vanillin (1.717 g), acetone (0.3 g) and then EtOH (3.16 g) are introduced into the reactor. The reaction mixture is kept at 45 °C for a few minutes until the mixture becomes homogeneous. Then a 50% solution containing 2.7 g of sodium hydroxide (2.7 g) and 2.7 g of water is introduced within a few minutes until a white suspension is formed, which then changes from white to yellow and then the reaction mixture becomes homogeneous and reddish. Then the mixture is stirred at room temperature (25 °C) for 48 h until the mixture becomes blood - red. Then the compound of formula (IV’a) in the form of its sodium salt is obtained (which can be separated, for example, by filtration).

[0367] Then the pH meter probe was introduced into the reaction mixture containing (IV’a) in salt form, the pH of which was about 12.9. The latter was neutralized to a pH close to 7 (pH = 7.2) by adding an organic or inorganic acid such as aqueous HCl (concentration approximately 4 M). Next, 20 ml of ethyl acetate (EtOAc) was added, and then the mixture was transferred to a separating funnel (stirred, decanted), and the aqueous phase was extracted with 2×EtOAc (2×20 ml), followed by drying over MgSO4, filtering, and concentrating under vacuum. Optionally, the crude product can be purified by silica gel chromatography: 80 g column, eluent: 80:20 heptane / EtOAc to 60:40. The orange solid corresponding to compound (Iv’a) was isolated, and its chemical structure was confirmed by conventional spectroscopic and spectrometric methods.

[0368] Step 2: The compound (IV’a) can then be hydrogenated under the same conditions as in step 2) of Example 1 in order to produce Compound (IV’a-reduced) 。

[0369]

Claims

1. A method for preparing at least one compound of formula (I): In formula (I): -R 1 represents a straight-chain or branched-chain, saturated or unsaturated hydrocarbon group having 1 to 6 carbon atoms; preferably, R 1 represents a C1-C4 alkyl group, more preferably a C2-C4 alkyl group such as ethyl; -R 2 represents a hydrogen atom or a C2-C4 alkyl group such as methyl or ethyl; preferably, R 2 represents a hydrogen atom; -R 3 represents a straight-chain or branched, saturated or unsaturated hydrocarbon group containing 1 to 12 atoms, optionally substituted by aryl; the aryl is preferably phenyl optionally substituted by one or more groups selected from hydroxy, C1-C4 alkyl, C1-C4 alkoxy and combinations thereof; preferably, R 3 represents C1-C6 alkyl; preferably C1-C4 alkyl; and also one of its optical isomers or geometric isomers, and / or one of its salts with an organic or inorganic acid or base, and / or one of its solvates such as a hydrate; The method is carried out according to the following synthesis scheme ( 1 ): ■ In the synthesis pathway ( 1 ): - X represents a heteroatom selected from oxygen and sulfur, preferably an oxygen atom, -R 1 , R 2 and R 3 have the same meanings as in formula (I); The method is characterized in that the method comprises: - at least one step (i) of reacting a compound of formula (II) in the presence of: ○ at least one compound of formula (III), ○ at least one (non)polar (non)protic solvent, and ○ at least one basic agent in an amount in excess of the molar amount of the compound of formula (II), so as to form at least one precipitate, the at least one precipitate comprising at least one compound of formula (IV), its geometric isomer and / or one of its salts with an organic or inorganic base; and - at least one step (i1) of separating the precipitate from the reaction medium of step (i), and then - at least one step (i2) of acidifying the precipitate with at least one inorganic or organic, preferably inorganic acidifying agent, followed by reaction step (ii).

2. The method according to claim 1, wherein The basic agent of step (i) is an inorganic basic agent selected from the group consisting of: alkali metal hydroxides or alkaline earth metal hydroxides, alkali metal hydrogencarbonates or alkaline earth metal hydrogencarbonates, and mixtures thereof, especially alkali metal hydroxides or alkaline earth metal hydroxides, especially sodium hydroxide.

3. The method according to any one of claims 1 to 2, characterized in that, Step (i) includes the reaction of: - at least one compound of formula (II), wherein R 1 and X have the same meanings as those indicated in claim 1, ○ Preferably, in formula (II), X represents an oxygen atom, in the presence of: - at least one compound of formula (III), wherein R 2 and R 3 have the same meanings as those indicated in claim 1, ○ Preferably, in formula (III), R 2 represents a hydrogen atom and R 3 represents a C1-C6 alkyl group, preferably a C1-C4 alkyl group, preferably methyl or ethyl; ○ Advantageously, the compound of formula (III) is present in the reaction medium of step (i) in an amount less than or equal to 5 molar equivalents, more preferably in an amount ranging from 2 to 5 molar equivalents, still better in an amount ranging from 2.5 to 5 molar equivalents, especially in an amount of 4.5 molar equivalents, relative to the compound of formula (II) so as to improve the kinetics of reaction step (i); - at least one (non)polar (non)protic solvent, preferably at least one polar protic solvent such as water, ○ Preferably, as a mixture with: at least one (non)polar (non)protic organic solvent, preferably a (non)polar aprotic organic solvent such as a nonpolar aprotic organic solvent, the nonpolar aprotic organic solvent preferably having a dielectric constant E in the range from 1 to 11 and a dipole moment μ in the range from 0 to 2, especially those selected from the group consisting of: n-hexane, cyclohexane, 1,4-dioxane, carbon tetrachloride (CCl4), benzene, tetrachloroethylene (Cl2C═Cl2C), toluene, carbon disulfide (CS2), trichloroethylene (Cl2C═CHCl), diethyl ether (Et2O), ethyl acetate (CH3C(O)OEt or AcOEt), dimethyl ether (DME), tetrahydrofuran (THF), methyltetrahydrofuran (2-MeTHF), dichloromethane (CH2Cl2), dichloroethane (ClCH2CH2Cl) and mixtures thereof; - at least one organic or inorganic, preferably inorganic basic agent, ○ More preferably, the base agent is selected from the group consisting of: alkali metal hydroxides or alkaline earth metal hydroxides, alkali metal carbonates (hydrogencarbonates) or alkaline earth metal carbonates (hydrogencarbonates), and mixtures thereof, especially alkali metal hydroxides or alkaline earth metal hydroxides, especially sodium hydroxide; - The base agent is in an excess molar amount relative to the compound of formula (II), ○ Preferably, the amount of the base agent is greater than or equal to 2 molar equivalents relative to the compound of formula (II), more preferably in the range from 2 to 5 molar equivalents, for example 4.5 molar equivalents.

4. The method according to any one of the preceding claims, characterized in that, The reaction step (i) is carried out at a temperature of less than or equal to 40 °C, preferably at a temperature in the range from 20 °C to 35 °C, more preferably at a temperature in the range from 25 °C to 35 °C, especially at a temperature of 30 °C ± 1 °C.

5. The method according to any one of the preceding claims, characterized in that, Once the reaction step (i) is completed, the reaction medium is cooled to a temperature of less than or equal to 25 °C, preferably in the temperature range from 1 °C to 12 °C, preferably in the range from 3 °C to 8 °C.

6. The method according to any one of the preceding claims, characterized in that, The step (i1) of separating the precipitate from the reaction medium of step (i) is carried out by filtration, preferably by pressure filtration.

7. The method according to any one of the preceding claims, characterized in that, The acidification step (i2) is carried out by means of at least one inorganic acidifying agent, preferably an inorganic acidifying agent of the H + Hal - type, where Hal represents a halogen atom selected from the group consisting of chlorine, bromine and iodine, and more preferably, the acidifying agent is hydrochloric acid.

8. The method according to any one of the preceding claims, characterized in that, After steps (i1) and (i2) have been carried out, before carrying out step (ii), the compound of formula (IV) is dissolved in at least one (non)-polar aprotic organic solvent, optionally as a mixture with at least one polar protic solvent such as water, preferably at least one non-polar aprotic organic solvent.

9. The method according to claim 8, when the compound of formula (IV) is dissolved in at least one (non)-polar aprotic organic solvent, the pH of the reaction medium is greater than 5.

10. The method according to any one of the preceding claims, characterized in that, Step (ii) is reduction by catalytic hydrogenation or reduction by a reducing agent selected from alkali metal hydrides such as alkali metal borohydrides such as NaBH4, alkali metal aluminum tetrahydrides such as LiAlH4. Preferably, the catalyst is present in the reaction medium of step (ii) in an amount in the range from 0.05% to 10%, preferably in the range from 0.1% to 10% by weight, preferably in the range from 0.5% to 1% by weight, based on the total weight of the reaction medium of step (ii).

11. The method according to any one of the preceding claims, characterized in that, Step (ii) is preferably reduction by catalytic hydrogenation with palladium (Pd), for example palladium on carbon (Pd / C), especially in the presence of at least one base agent having a pKa in the range from 8 to 11, preferably from 9 to 11, especially from 9 to 10, preferably selected from the group consisting of alkali metal carbonates (hydrogencarbonates) or alkaline earth metal carbonates (hydrogencarbonates) and mixtures thereof.

12. The method according to claim 10 or 11, characterized in that, At the end of step (ii), the compound of formula (I) is purified by short-path distillation.

13. The method according to any one of the preceding claims, characterized in that, In formula (I), R 2 represents a hydrogen atom and / or R 1 represents a straight-chain or branched-chain, preferably straight-chain C1-C4 alkyl group, more preferably a straight-chain C2-C4 alkyl group such as ethyl and / or R 3 represents a straight-chain or branched-chain C1-C6 alkyl group.

14. The method according to any one of the preceding claims, characterized in that, In formula (I), R 1 represents a C1-C4 alkyl group, more preferably a C2-C4 alkyl group such as ethyl; R 2 represents a hydrogen atom; R 3 represents a C1-C6 alkyl group; preferably a C1-C4 alkyl group, more preferably a C1-C3 alkyl group, especially a C1 alkyl group.

15. A compound of the following formula (I’): In formula (I’): -R 1 represents a straight-chain or branched-chain, saturated or unsaturated hydrocarbon group having 1 to 6 carbon atoms; preferably, R 1 represents a C1-C4 alkyl group, more preferably a C2-C4 alkyl group such as ethyl; -R 2 represents a hydrogen atom or a C2-C4 alkyl group such as methyl or ethyl; preferably, R 2 represents a hydrogen atom; -R 3 represents a branched, saturated or unsaturated hydrocarbon group containing from 1 to 12 atoms; preferably, R 3 represents a branched, saturated or unsaturated hydrocarbon group containing from 3 to 12 carbon atoms; more preferably R 3 represents a branched C1-C6 alkyl group, more preferably R 3 represents a branched C3-C6 alkyl group; in particular, R 3 represents a branched C3-C4 alkyl group, especially a branched C4 alkyl group; And also one of its optical isomers or geometric isomers, and / or one of its salts with an organic or inorganic acid or base, and / or one of its solvates such as hydrates.

16. A compound of formula (I) or (I'), obtainable by the method according to any one of claims 1 to 14, and / or one of its optical or geometric isomers, and / or one of its salts with an organic or inorganic acid or base, and / or one of its solvates such as a hydrate.

17. A composition, characterized in that, The composition comprises at least one compound of formula (I) or (I') obtainable by the method according to any one of claims 1 to 14, and / or one of its optical or geometric isomers, and / or one of its salts with an organic or inorganic acid or base, and / or one of its solvates such as a hydrate.

18. The composition according to the preceding claim, characterized in that, The compound of formula (I) or (I') is present in an amount greater than 10% by weight relative to the total weight of the composition.

19. The composition according to claim 17 or 18, characterized in that, The composition further comprises at least one (non)polar (non)protic organic solvent, preferably a polar protic organic solvent, and optionally water.

20. The composition according to the preceding claim, characterized in that, The (non)-polar (non)-protic organic solvent, preferably the polar protic organic solvent, is selected from the group consisting of (C2-C 10 ) alkane (poly)ols, preferably (C2-C6) alkane (poly)ols.

21. The composition according to any one of claims 17 to 20, characterized in that, The composition comprises: - at least one compound of formula (I) or (I') obtainable by the method according to any one of claims 1 to 14, which is present in a content ranging from 75% to 95% by weight relative to the total weight of the composition, - at least one (non)polar (non)protic organic solvent as defined in claim 19 or 20, in an amount ranging from 5% to 20% by weight relative to the total weight of the composition, - water which can be present in a content ranging from 0.05% to 5% by weight relative to the total weight of the composition.

22. The composition according to any one of claims 17 to 21, characterized in that, The composition consists of: i) 90% + / - 5% by weight of a compound of formula (I) or (I') obtainable by the method according to any one of claims 1 to 15; ii) 9% + / - 2% by weight of a polar protic organic solvent, especially a polyol, preferably a (C2-C6) alkylene diol, more preferably selected from the group consisting of propane-1,2-diol, propane-1,3-diol, butanediol and mixtures thereof, even more preferably 1,3-propanediol; and 1% + / - 0.5% by weight of water, provided that the sum of components i) + ii) + iii) is equal to 100%.

23. A compound of the following formula (IV'), its reduced form (IV' reduced), and also one of its optical or Z / Z, Z / E, E / Z and E / E geometric isomers, and / or one of its salts with an organic or inorganic acid or base, and / or one of its solvates such as a hydrate: In formula (IV') or (IV' reduced): -R 1 represents a straight-chain or branched-chain, saturated or unsaturated hydrocarbon group having 1 to 6 carbon atoms; preferably, R 1 represents a C1-C4 alkyl group, more preferably a C2-C4 alkyl group such as ethyl; -R 2 represents a hydrogen atom or a C2-C4 alkyl group such as an ethyl group; preferably, R 2 represents a hydrogen atom; Preferably, the compound of formula (IV') or (IV' reduced) is obtainable by the method according to any one of claims 1 to 12.

24. A composition which comprises in a physiologically acceptable medium one or more compounds of formula (IV') according to the previous claim, and also their optical or Z / Z, Z / E, E / Z and E / E geometric isomers, and / or their salts with an organic or inorganic acid or base, and / or their solvates such as hydrates.

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